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IWO Meeting 16 November 2022 - Tumor-induced osteomalacia: a systematic clinical review of 895 cases
- 1. TUMOR-INDUCED OSTEOMALACIA A Systematic Clinical Review of 895 Cases A.Bosman, MD, PhD candidate Internal Medicine Erasmus MC, Rotterdam, the Netherlands September 8, 2022: ASBMR symposium on rare diseases: From molecules and mechanisms to therapeutics (abstract 645) Bosman A, Palermo A, Vanderhulst J, De Beur SMJ, Fukumoto S, Minisola S, Xia W, Body JJ, Zillikens MC. Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases. Calcif Tissue Int. 2022 Jul 20. doi: 10.1007/s00223-022-01005-8. Epub ahead of print. PMID: 35857061. Copyright A. Bosman
- 2. (potentiële) belangenverstrengeling Geen / Zie hieronder Voor bijeenkomst mogelijk relevante relaties met bedrijven Bedrijfsnamen • Sponsoring of onderzoeksgeld • Honorarium of andere (financiële) vergoeding • Aandeelhouder • Andere relatie, namelijk … • Health ~ Holland (PhosphoNorm; LSHM18029). • • • Disclosurebelangenspreker Copyright A. Bosman
- 3. At the outpatient clinic Male, 56 years Married, three children, mechanician Referred to outpatient clinic with recent vertebral fracture and fracture of the foot Progressive muscle weakness and bone pain, since three years Serum TSH, total calcium, albumin, kreatinine, 25(OH)D and PTH: normal Serum phosphate: 0.35 mmol/L (Normal: 0.80-1.40 mmol/L) Copyright A. Bosman
- 5. Differentiaal diagnose hypofosfatemie Imel EA et al. JCEM 2012 Copyright A. Bosman
- 6. Tumor-induced osteomalacia (TIO) • FGF23-producing mesenchymal tumor, typically benign • Prevalence 0.7/100.000 (Danish observational cohort study) • Presentation: • Children: rickets (gait disturbances, growth retardation, skeletal deformities) • Adults: muscle weakness, pain, osteomalacia • Diagnosis • hypophosphatemia, phosphaturia (low TmP/GFR), low or inappropriately normal serum 1.25(OH)2 D • Localization of the tumor with imaging • Treatment: tumor removal or medical treatment (phosphate, active vitamine D or burosumab) Initial presentation can be misleading or non-specific. Long diagnostic delay, advanced disability Abrahamsen et al. 2021 Calcified Tissue International Copyright A. Bosman
- 7. Systematic clinical review Systematic search in Pubmed, Embase and Web of Science (WOS): Oncogenic osteomalacia OR oncogenous osteomalacia OR Rickets, Hypophosphatemic OR hypophosphatemic rickets OR tumor-induced osteomalacia OR tumor-induced rickets OR oncogenic rickets Data collection: • Demographic characteristics: age, sex • Biochemical characteristics: serum phosphate, 25(OH)D, 1.25(OH)2 D, FGF23, TmP/GFR • Tumor-related characteristics: location, size, identification techniques, diagnostic delay • Clinical characteristics: symptoms, bone health (BMD, fractures) Inclusion: • Reported serum phosphate level before treatment • Known tumor localization (cure after appropriate treatment or at least clear-cut improvement). Copyright A. Bosman
- 9. Demographic characteristics N Result Sex - Male - Female 858 500 359 58.3% 41.7% Age (median, range) - <18 years (%) - =/> 18 (%) 868 39 829 45.2 (15.1) 4.5% 95.5% Copyright A. Bosman
- 10. Tumor localization Osteomalacia related symptoms in 89.9% Local symptoms in 8.3% Tumor localization by clinical evaluation in • 38.7% of cases with a reported physical examination • 21.3% of the whole population Copyright A. Bosman
- 11. Biochemistry ULN = the times the upper limit of normal of FGF23 Copyright A. Bosman
- 12. FGF23 and tumor size Copyright A. Bosman
- 14. BMD and fractures N Median (IQR) BMD L1-L4 (T-score) - Osteoporosis (T<-2.5) 99 61 -2.87 (1.45) 61.6% BMD total hip (T-score) - Osteoporosis (T<-2.5) 33 25 -2.83 (1.25) 75.8% BMD femoral neck (T-score) - Osteoporosis (T<-2.5) 48 33 -2.82 (1.39) 68.8% N Fracture data - No fractures - Vertebra - Hip - Rib - Wrist - Other 422 77 (18.2%) 133 (27.0%) 196 (39.8%) 178 (36.1%) 10 (2.0%) 155 (31.4%) Copyright A. Bosman
- 15. Conclusions • Low phosphate can lead to significant disabilities, one of the causes is TIO • TIO is caused by an FGF23 producing tumor, leading to hypophosphatemia and osteomalacia related and/or local complaints • Presentation at any age, majority of TIO in adults 40-60 yrs • Bone fragility represents a hallmark of this disease • Localization: anywhere but most often lower limbs (46%) and head and neck area (26%). • FGF23 is related to tumor size importance of early detection followed by removal. • Considerable diagnostic delay despite increased knowledge and improved imaging techniques, Copyright A. Bosman
- 16. Acknowledgements Erasmus MC, University Medical Center Rotterdam, The Netherlands, Department of Internal Medicine. Prof. dr. M.C. Zillikens Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy Dr. Andrea Palermo Department of Medicine, CHU Brugmann, Université Libre de Bruxelles (ULB), Brussels, Belgium. Dr. Julien Vanderhulst Prof. dr. Jean-Jacques Body Johns Hopkins University School of Medicine, Baltimore, MD, USA Prof. dr. S. Jan De Beur Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan Prof. dr. S. Fukumoto Department of Clinical, Internal, Anesthesiological and Cardiological Sciences, "Sapienza" Rome University, 00161 Rome, Italy Prof. dr. S. Minisola Department of Endocrinology, Key Laboratory of Endocrinology, The National Commission of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China Prof. dr. W. Xia Copyright A. Bosman
- 18. Phosphate Phosphate functions mag evt weg • Bone mineralization • Component of DNA/RNA • Role in biological systems Storage in bone Hypophosphatemia: zou je niet dd van hyposfosfataemie toevoegen? • rickets/osteomalacia • bone pain • proximal myopathy Regulating hormones: 1.25(OH)2D, PTH, FGF23 kort schema?, bijna niemand in zaal kent fgf23!!! Campos-Obando et al. 2018 Eur J Epidemiol Leung et al. 2019. J. Clin. Pathol. Copyright A. Bosman
- 19. Methods Inclusion: • Reported serum phosphate level before treatment • Known tumor localization (cure after appropriate treatment or at least clear-cut improvement). Exclusion: • Hypophosphatemia from unknown cause • TIO-like syndrome (e.g., linear sebaceous naevi, von Recklinghausen disease, fibrous dysplasia of bone, McCune-Albright syndrome) Statistical analysis: descriptive statistics (mean, SD, median, IQR), Mann Whitney-U test, Kruskal- Wallis test, Spearman’s correlations Copyright A. Bosman